Gross Oliver, Tönshoff Burkhard, Weber Lutz T, Pape Lars, Latta Kay, Fehrenbach Henry, Lange-Sperandio Baerbel, Zappel Hildegard, Hoyer Peter, Staude Hagen, König Sabine, John Ulrike, Gellermann Jutta, Hoppe Bernd, Galiano Matthias, Hoecker Britta, Ehren Rasmus, Lerch Christian, Kashtan Clifford E, Harden Markus, Boeckhaus Jan, Friede Tim
Clinic for Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany.
Department of Pediatrics I, University Children's Hospital Heidelberg, Heidelberg, Germany.
Kidney Int. 2020 Jun;97(6):1275-1286. doi: 10.1016/j.kint.2019.12.015. Epub 2020 Jan 17.
Children with Alport syndrome develop renal failure early in life. Since the safety and efficacy of preemptive nephroprotective therapy are uncertain we conducted a randomized, placebo-controlled, double-blind trial in 14 German sites of pediatric patients with ramipril for three to six years plus six months follow-up to determine these parameters. Pretreated children and those whose parents refused randomization became an open-arm control, which were compared to prospective real-world data from untreated children. The co-primary endpoints were safety (adverse drug reactions) and efficacy (time to progression). Out of 66 oligosymptomatic children, 22 were randomized and 44 joined the open-arm comparison. Ramipril therapy showed no safety issues (total of 216.4 patient-years on ramipril; adverse event rate-ratio 1.00; 95% confidence interval 0.66-1.53). Although not significant, our results cautiously showed that ramipril therapy was effective: in the randomized arm, Ramipril decreased the risk of disease progression by almost half (hazard ratio 0.51 (0.12-2.20)), diminished the slope of albuminuria progression and the decline in glomerular filtration. In adjusted analysis, indications of efficacy were supported by prospective data from participants treated open label compared with untreated children, in whom ramipril again seemed to reduce progression by almost half (0.53 (0.22-1.29)). Incorporating these results into the randomized data by Bayesian evidence synthesis resulted in a more precise estimate of the hazard-ratio of 0.52 (0.19-1.39). Thus, our study shows the safety of early initiation of therapy and supports the hope to slow renal failure by many years, emphasizing the value of preemptive therapy. Hence, screening programs for glomerular hematuria in children and young adults could benefit from inclusion of genetic testing for Alport-related gene-variants.
患有奥尔波特综合征的儿童在幼年时就会出现肾衰竭。由于抢先进行的肾保护治疗的安全性和有效性尚不确定，我们在德国的14个地点对儿科患者进行了一项随机、安慰剂对照、双盲试验，给予雷米普利治疗三至六年，并进行六个月的随访以确定这些参数。经过预处理的儿童以及其父母拒绝随机分组的儿童成为开放组对照，将其与未接受治疗儿童的前瞻性真实世界数据进行比较。共同主要终点是安全性（药物不良反应）和有效性（疾病进展时间）。在66名症状轻微的儿童中，22名被随机分组，44名加入开放组对照。雷米普利治疗未显示出安全性问题（雷米普利治疗的总患者年数为216.4；不良事件率比为1.00；95%置信区间为0.66-1.53）。尽管结果不显著，但我们的研究谨慎地表明雷米普利治疗是有效的：在随机分组组中，雷米普利使疾病进展风险降低了近一半（风险比为0.51（0.12-2.20）），减小了蛋白尿进展的斜率以及肾小球滤过率的下降。在调整分析中，与未接受治疗的儿童相比，接受开放标签治疗的参与者的前瞻性数据支持了有效性指标，在未接受治疗的儿童中，雷米普利似乎再次使疾病进展降低了近一半（0.53（0.22-1.29））。通过贝叶斯证据合成将这些结果纳入随机数据中，得出了更精确的风险比估计值0.52（0.19-1.39）。因此，我们的研究显示了早期开始治疗的安全性，并支持了将肾衰竭延缓多年的希望，强调了抢先治疗的价值。因此，儿童和年轻人的肾小球性血尿筛查项目可能会受益于纳入与奥尔波特相关基因变异的基因检测。
